1. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin1 054402 Design and Analysis II LECTURE 2: PROCESS CREATION Daniel R. Lewin Department of Chemical Engineering Technion, Haifa, Israel

2. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin2 Objectives  Understand how to go about assembling design data and creating a preliminary data base.  Be able to implement the steps in creating flowsheets involving reactions, separations, and T-P change operations. In so doing, many alternatives are identified that can be assembled into a synthesis tree that contains the most promising alternatives.  Know how to select the principal pieces of equipment and to create a detailed process flowsheet, with a material and energy balance and a list of major equipment items. On completing this part of the course, you should:

3. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin3 Schedule - Process Creation  Preliminary Database Creation –to assemble data to support the design.  Experiments –often necessary to supply missing database items or verify crucial data.  Preliminary Process Synthesis –top-down approach. –to generate a “synthesis tree” of design alternatives. –illustrated by the synthesis of processes for the manufacture of VCM and tPA.  Development of Base-case Design –focusing on the most promising alternative(s) from the synthesis tree. Ref: Seider, Seader and Lewin (1999), Chapter 2

4. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin4 Preliminary Database Creation  Thermophysical property data –physical properties –phase equilibria (VLE data) –Property prediction methods  Environmental and safety data –toxicity data –flammability data  Chemical Prices –e.g. as published in the Chemical Marketing Reporter  Experiments –to check on crucial items above

5. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin5 Preliminary Process Synthesis  Synthesis of chemical processes involves:  Selection of processing mode: continuous or batch  Fixing the chemical state of raw materials, products, and by- products, noting the differences between them.  Process operations (unit operations) - flowsheet building blocks  Synthesis steps -  Eliminate differences in molecular types  Distribute chemicals by matching sources and sinks  Eliminate differences in composition  Eliminate differences in temperature, pressure and phase  Integrate tasks (combine tasks into unit operations)

6. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin6 Continuous or batch processing? Continuous Batch Fed-batch Batch-product removal

7. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin7 The Chemical State  Decide on the raw material and product specifications (states):  Mass (flow rate)  Composition (mole or mass fraction of each chemical species having a unique molecular type)  Phase (solid, liquid, or gas)  Form (e.g., particle-size distribution and particle shape)  Temperature  Pressure

8. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin8 Process Operations (“Lego”)  Chemical reaction –Positioning in the flowsheet involves many considerations (conversion, rates, etc.), related to T and P at which the reaction are carried out.  Separation of chemicals –needed to resolve difference between the desired composition of a product stream and that of its source. Selection of the appropriate method depends on the differences of the physical properties of the chemical species involved.  Phase separation  Change of temperature  Change of pressure  Change of phase  Mixing and splitting of streams and branches

9. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin9 Synthesis Steps Synthesis Step  Eliminate differences in molecular types  Distribute chemicals by matching sources and sinks  Eliminate differences in composition  Eliminate differences in temperature, pressure and phase  Integrate tasks (combine tasks into unit operations)  Process Operation  Chemical reaction  Mixing  Separation  Temperature, pressure and phase change

10. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin10 Example 1: Vinyl Chloride Manufacture Process Creation

11. DESIGN AND ANALYSIS II - (c) Daniel R. Lewin11  Eliminate differences in molecular types Chemicals participating in VC Manufacture:

12. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin12  Direct chlorination of ethylene: Selection of pathway to VCM (1) Advantages: –Attractive solution to the specific problem denoted as Alternative 2 in analysis of primitive problem. –Occurs spontaneously at a few hundred o C. Disadvantages: –Does not give a high yield of VC without simultaneously producing large amounts of by-products such as dichloroethylene –Half of the expensive chlorine is consumed to produce HCl by- product, which may not be sold easily. (2.1)

13. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin13  Hydrochlorination of acetylene: Selection of pathway to VCM (2) Advantages: –This exothermic reaction is a potential solution for the specific problem denoted as Alternative 3. It provides a good conversion (98%) of C 2 H 2 VC in the presence of HgCl 2 catalyst impregnated in activated carbon at atmospheric pressure. –These are fairly moderate reaction conditions, and hence, this reaction deserves further study.  Disadvantages: –Flammability limits of C 2 H 2 (2.5  100%) (2.2)

14. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin14  Thermal cracking of C 2 H 4 Cl 2 from chlorination of C 2 H 4 : Selection of pathway to VCM (3) Advantages: –Conversion of ethylene to 1,2-dichloroethane in exothermic reaction (2.3) is  98% at 90 o C and 1 atm with a Friedel-Crafts catalyst such as FeCl 3. This intermediate is converted to vinyl chloride by thermal cracking according to the endothermic reaction (2.4), which occurs spontaneously at 500 o C with conversions as high as 65% (Alternative 2). Disadvantage: –Half of the expensive chlorine is consumed to produce HCl by-product, which may not be sold easily. (2.3) (2.4) (2.1)

15. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin15  Thermal Cracking of C 2 H 4 Cl 2 from Oxychlorination of C 2 H 4 : Selection of pathway to VCM (4) Advantages: –Highly exothermic reaction (2.5) achieves a 95% conversion to C 2 H 4 Cl 2 in the presence of CuCl 2 catalyst, followed by pyrolysis step (2.4) as Reaction Path 3. –Excellent candidate when cost of HCl is low –Solution for specific problem denoted as Alternative 3.  Disadvantages: –Economics dependent on cost of HCl (2.5) (2.4) (2.6)

16. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin16  Balanced Process for Chlorination of Ethylene: Selection of pathway to VCM (5) Advantages: –Combination of Reaction Paths 3 and 4 - addresses Alternative 2. –All Cl 2 converted to VC –No by-products! (2.5) (2.3) (2.7) (2.4)

17. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin17 Evaluation of Alternative Pathways Chemical Bulk Prices  Reaction Path  is eliminated due its low selectivity.  This leaves four alternative paths, to be compared first in terms of Gross Profit.

18. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin18 Computing Gross Profit Gross profit = 22(1) + 18(0.583) - 18(0.449) - 11(1.134) = 11.94 cents/lb VC

19. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin19 Preliminary Flowsheet for Path   800 MM lb/year @ 330 days/y  100,000 lb/hr VC  On the basis of this principal sink, the HCl sink and reagent sources can be computed (each flow is 1,600 lbmol/h)  Next step involves distributing the chemicals by matching sources and sinks.

20. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin20  Distribute the chemicals  A conversion of 100% of the C 2 H 4 is assumed in the chlorination reaction.

21. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin21  Distribute the chemicals  Only 60% of the C 2 H 4 Cl 2 is converted to C 2 H 3 Cl with a byproduct of HCl, according to Eqn. (2.4).  To satisfy the overall material balance, 158,300 lb/h of C 2 H 4 Cl must produce 100,000 lb/h of C 2 H 3 Cl and 58,300 lb/h of HCl.  But a 60% conversion only produces 60,000 lb/h of VC.  The additional C 2 H 4 Cl 2 needed is computed by mass balance to equal: [(1 - 0.6)/0.6] x 158,300 or 105,500 lb/h.  Its source is a recycle stream from the separation of C 2 H 3 Cl from unreacted C 2 H 4 Cl 2, from a mixing operation, inserted to combine the two sources, to give a total 263,800 lb/h.

22. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin22  Distribute the chemicals  The effluent stream from the pyrolysis operation is the source for the C 2 H 3 Cl product, the HCl by-product, and the C 2 H 4 Cl 2 recycle.

23. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin23  Reactor pressure levels: –Chlorination reaction: 1.5 atm is recommended, to eliminate the possibility of an air leak into the reactor containing ethylene. –Pyrolysis reaction: 26 atm is recommended by the B.F. Goodrich patent (1963) without any justification. Since the reaction is irreversible, the elevated pressure does not adversely affect the conversion. Most likely, the patent recommends this pressure to reduce the size of the pyrolysis furnace, although the tube walls must be considerably thicker and many precautions are necessary for operation at elevated pressures. –The pressure level is also an important consideration in selecting the separation operations, as will be discussed in the next synthesis step.  Distribute the chemicals

24. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin24  The product of the chlorination reaction is nearly pure C 2 H 4 Cl 2, and requires no purification.  In contrast, the pyrolysis reactor conversion is only 60%, and one or more separation operations are required to match the required purities in the C 2 H 3 Cl and HCl sinks.  One possible arrangement is given in the next slide. The data below explains the design decisions made.  Eliminate Differences in Composition

25. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin25  Eliminate Differences in Composition There may be other, possibly better alternative configurations, as discussed in Lecture 4 (Chapter 5).

26. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin26  Eliminate differences in T, P and phase

27. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin27  Integrate tasks (tasks  unit operations)

28. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin28 Assembly of synthesis tree      Reaction path Distribution of chemicals Separations T, P and phase changes Task integration Algorithmic methods are very effective for the synthesis, analysis and optimization of alternative flowsheets. These will be covered in Section B (Part II)

29. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin29 Development of Base-case Design  Develop one or two of the more promising flowsheets from the synthesis tree for more detailed consideration.

30. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin30 Example 2: Manufacture of Tissue Plasmonigen Activator Process Creation

31. DESIGN AND ANALYSIS II - (c) Daniel R. Lewin31 tPA is tissue plasminogen activator A recombinant, therapeutic protein - comprised of 562 amino acids Manufacture of tPA

32. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin32  tPA activates plasminogen – to plasmin (an enzyme)  plasmin dissolves fibrin formations that hold blood clots in place  blood flow is re-established once the clot blockage dissolves  important for patients with heart attacks (myocardial infarction) or stroke Manufacture of tPA Pharmacology:  has been produced by Genentech (Activase TM ) since 1986  sells for $2,000/100 mg dose  2003 – Patent protection expires  Design objective – manufacture generic form of tPA to sell for $200/dose Business Strategy:

33. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin33 Process Synthesis Problem

34. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin34 Identify Reaction Paths – with help from the Biochemist 1. Mammalian Cells tPA-DNA sequence + CHO cells  selected high expressing PA-CHO cells (1) (1-10 mg from (10 6 cells) (CHO cells with human melanoma tPA-DNA inserted cells) in their genomes) Selected tPA-CHO cells (“founder cells”) amplified to yield about 10 6 cells/mL – during R&D stage. These cells are frozen into 1-mL aliquots at - 70  C.  Eliminate differences in molecular types

35. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin35 Prepared in laboratory – stored in 1 mL aliquots at - 70°C Used as inoculum for the bio-reaction: tPA-CHO cells + HyQ PF-CHO media + O 2  Increased cell nos. (2) 0.39  10 6 cells/mL-day 50 pg tPA/cell-day 0.2  10 -12 mol O 2 /cell-hr Rates from Genentech patent (1988) As tPA-CHO cells reproduce, tPA secretes into liquid media solution.  Eliminate differences in molecular types

36. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin36 Project cost of chemicals produced or sold ChemicalKg/Kg tPACost, $/Kg tPA12,000,000  HyQ PF CHO powder media 287.2233 Water for injection (WFI) 2,2280.12 + Air46.81,742 CO 2 3.71,447 tPA-CHO cells-*  $200/100 mg dose + $0.45/gal = $450/1,000 gal * Not included in gross profit estimate – related to cost of research, an operating cost. Computing Gross Profit

37. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin37 Gross Profit = 2,000,000 – 287.2  233 – 2,228  0.12 -3.7  1,447 – 46.8  1,742 = $1,846,000/Kg tPA Computing Gross Profit Does not include operating costs (cost of research and cost of utilities) and investment cost - yet, high for a pharmaceutical - process synthesis proceeds at an accelerated pace

38. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin38 Insert Reaction Operations into Flowsheet

39. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin39  Distribute the chemicals

40. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin40 tPA protein must be recovered from other proteins, cell debris, media, water, and gas emissions Proteins lose activity (denature) at temperatures above ~ 0  C Hence - entire separation process designed to operate at 4  C, slightly above freezing point of water.  Eliminate Differences in Composition

41. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin41  Eliminate Differences in Composition

42. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin42  Eliminate differences in Temperature

43. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin43  Integrate tasks (tasks  unit operations)  Equipment items are selected – often combining operations into a single equipment item batchcontinuous  Key decision – batch or continuous operation  80 Kg/yr tPA – batch mode  Select equipment sizes to produce 1.6 Kg/batch  i.e., 80/1.6 = 50 batch/yr  To allow for separation losses, produce 2.24 Kg/batch in the cultivators  Using 5,000 L vessel, 14 day/batch = cycle time  Hence, run two batch trains in parallel  each producing 25 batch/yr

44. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin44  Task Integration – Reactor Section

45. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin45  Task Integration – Separation Section

46. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin46 tPA - Synthesis Tree

47. Process CreationDESIGN AND ANALYSIS II - (c) Daniel R. Lewin47 Process Creation - Summary Next week: Process Design Heuristics  Preliminary Database Creation –needed to provide data to support the design.  Experiments –often necessary to supply missing database items or verify crucial data.  Preliminary Process Synthesis –top-down approach. –generates a “synthesis tree” of design alternatives. –illustrated by the synthesis of the VCM and tPA processes.  Development of Base-case Design –focusing on the most promising alternative(s) from the synthesis tree.